The objective of this renewal application is three-fold. First, we plan to capitalize on our accomplishments in the last 10 years and provide a comprehensive dissection of the contribution of age-related changes in other organs or tissues (e.g., ovaries, bone marrow, adrenals), and the cellular and molecular mechanisms behind them, to the age-related loss of bone mass and strength versus the contribution of skeletal aging per se. Second, we will establish the impact of aging on various qualitative aspects of bone strength, including microarchitecture, prevalence of fatigue damage, bone turnover, and osteocyte number. Third, we will investigate the relative efficacy and mechanistic appropriateness of different therapeutic modalities on the aging skeleton in the context of the specific pathogenetic factors that contribute to age-associated osteoporosis. To achieve the goal of the Program, four Projects (supported by three Cores) will address, in a thematic and systematic manner, closely interrelated hypotheses, which will be tested using a variety of molecular and cell biology approaches, as well as normally aging C57BL/6 mice, and several other transgenic and knockout mice. In Project 1, the contribution of estrogen loss to the age-related loss of bone mass and strength will be investigated by exploring the molecular mechanisms of the skeletal effects of estrogens in old age, and in particular, the compelling link among the antioxidant properties of estrogens, cytoplasmic kinase-mediated estrogen actions, reactive oxygen species, and the birth and death of bone cells with old age. Project 2 will examine the contribution of oxidized lipids (and the enzymes responsible for their generation, e.g., Alox15, or the transcription factors that mediate their actions, e.g., PPARy), to the decreased osteoblastogenesis and increased adipogenesis that occurs with old age;and the exciting possibility that daily injections of PTH are rational therapy for age-related osteoporosis because they ameliorate the adverse effects of reactive oxygen species and oxidized lipids on osteoblast apoptosis. Project 3 will seek a mechanistic explanation for why age is a far more critical risk factor for fractures than bone mineral density. Specifically, we will study the impact of the age-related increase in glucocorticoid production on the integrity of the osteocyte/lacunarcanalicular system, fluid flow, material properties and the accumulation of damaged bone;and the contribution of these factors on the mismatch between bone strength and BMD. Finally, Project 4 will explore the possibility that reduced mechanical forces during aging (from reduced physical activity) increase osteocyte apoptosis and this leads to deterioration of bone quality and an aberrant repair process, both of which contribute to decreased bone strength. This work should help us better understand why elderly people suffer from osteoporosis a lot more than young people;and perhaps identify the optimal anti-osteoporosis therapy for this particular segment of the population.